Prostaglandins are a sub-class of eicosanoids found in most body tissues and implicated in a variety of physiological functions in animals, including smooth muscle contraction, reproduction, autoimmunity, inflammation, reduction of intraocular pressure, etc. Prostaglandin E2 (PGE2) has been associated with various physiological and/or pathological conditions such as stimulation of bone formation, increase in bone mass, arthritis, pain, inflammation, cancer, multiple sclerosis, etc.
PGE2 binds to four receptors (EP1, EP2, EP3 and EP4). The EP4 receptor is associated with intracellular cyclic adenosine monophosphate (cAMP) production, and is distributed in a wide variety of tissue types suggesting a major role in PGE2-mediated biological events, such as smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
A variety of EP4 agonists have been described and include, without limitation, compounds as set forth in, for example, WO 02/24647, WO 02/42268, EP 1132086, EP 855389, EP 1114816, WO 01/46140, WO 01/72268, WO 05/116010, WO 03/047417, or U.S. Pat. No. 7,238,710. Many EP4 agonists have however been associated with systemic side effects.
Bisphosphonates are drugs used to strengthen bone and have been implicated in inhibiting bone resorption and bone targeting.
Prostaglandin-bisphosphonate conjugate compounds have been described in for example U.S. Pat. No. 5,409,911 or U.S. Pat. No. 6,121,253.